Green Chemistry and Microwave AssistedSynthesis: From Theory to Practices M A LabEmiliano Rosatelli, Sezione Chim. Farm. I S C Laboratory of Medicinal and Advanced Synthetic Chemistry Dipartimento di Chimica e Tecnologia del Farmaco Università degli Studi di Perugia Perugia - May 8, 2012
OverviewGreen chemistry: concept and principlesMicrowave assisted synthesis • Mechanism of microwave induced heating • “Greenness” of microwave synthesis • Examples
Role of a Synthetic (Medicinal) ChemistChemists are molecular designers: they design and synthesize new molecules and new materials
Role of a Synthetic Chemistry in Drug Development Obstacles in Drug Development From Concept to Pharmacy FDA Clinical Safety Formulation Scale-up ADME Patent In vivo efficacy Cellular efficacy SAR-potency-selectivity Screen to identified leadMolecular target selection
Role of Chemistry in Environmental ProblemsChemistry produces waste and contributes to environmental pollution necessity of environmentally sustainable chemistry GREEN CHEMISTRY
Green Chemistry = Responsibility GREEN CHEMISTRY Why is there no ‘Green Geology’ or ‘Green Astronomy’? Because chemistry is the science that introduces newsubstances into the world and we have a responsibility for their impact in the world.” Ronald Breslow
What’s Green Chemistry? The term green chemistry was coined by Paul Anastas in 1991. The green chemistry also called sustainable chemistry, is a philosophy of chemical research and engineering that encourages the design of products and processes that minimize the use and generation of hazardous substances.As a chemical philosophy, green chemistry can be applied to syntheticchemistry, inorganic and organic chemistry, medicinal chemistry,biochemistry, analytical chemistry, and even physical chemistry.
Green Chemistry Is About… Waste minimisation as source Waste Use of catalyst in place of reagents Materials Using non-toxic reagents reducing Hazard Use of renewable resources Risk Improved atom efficiency Energy Use of solvent free orrecyclable environmentally Cost benign solvent systems
The 12 Principles of Green Chemistry 1. Pollution Prevention 2. Atom Economy 3. Less Hazardous Chemical Synthesis 4. Designing Safer Chemicals 5. Safer Solvents and Auxiliaries 6. Design for Energy Efficiency 7. Use of Renewable Feedstocks 8. Reduce Derivatives 9. Catalysis 10. Design for Degradation 11. Real-Time Analysis for Pollution Prevention 12. Inherently Safer Chemistry for Accident Prevention
1. Pollution Prevention Recycling or reuse of raw materials Increase the efficiency of a process to reduce the amount of waste and pollution generated Use of less toxic, non-toxic or renewable substances as raw materialsIt is better to prevent waste than to treat or clean up waste after it is formed because: “Always better to prevent than to cure”
2. Atom Economy Low atom economy + + WasteRaw materials Product (by-products) High atom economy + Raw materials Product Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product “Waste not, we don’t want it!”
3. Less Hazardous Chemical Synthesis 4. Designing Safer Chemicals Less hazardous reagents and chemicals When possible, toxic or hazard chemicals can be replaced by safer ones Designing products that are safe and non-toxic, preserving their functionWhenever practicable, synthetic methodologies should bedesigned to use and generate substances that possess little or no toxicity to human health and the environment.
5. Safer Solvents and Auxiliaries Difficult to dispose Toxic Volatiles Organic solvents Flammable Corrosive Solvent-less system, water-based reaction Solvents should be natural, non-toxic, cheap, and readily available (green solvent) Using of supercritical fluid or ionic liquids The use of auxiliary substances (solvents, separation agents, etc.) should be made unnecessary whenever possible and, when used, innocuous.
6. Design for Energy Efficiency Energy consumption contributes to pollution. Unutilized energy may also be considered a waste ( 1st principle). Reducing the energy barrier of the chemical reaction and increasing its energy efficiency. Reactions performed at room temperature. Use of alternative energy sources as biofuels, solar power, wind power, hydro- power, geothermal energy and hydrogen cells. Energy requirements should be recognized for their environmental and economic impacts and should be minimized.
7. Use of Renewable Feedstocks 90-95% of the products we use (plastics, pharmaceuticals, energy) come from oil, a not renewable resource. A green chemistry approach provides the use of renewable raw materials deriving from living organisms: • wood • crops • agricultural residue • cellulose • starch • etc. etc..A raw material or feedstock should be renewable rather than depleting whenever technically and economically practical.
8. Reduce Derivatives A conventional chemical process involves several manipulations to transform the starting material to the desired product. Green chemistry approach provides to design products in a simplified manner avoiding, whenever possible, the blocking group, protection/deprotection or temporary modification of physical/chemical processesUnnecessary derivatization should be avoided whenever possible.
9. Catalysis Catalysts improve the efficiency Uncatalyzed of reaction Less feedstockCatalyzed Less waste Less energy consumption Catalytic reagents are superior to stoichiometric reagents
10. Design for Degradation Avoiding certain chemical structures: • halogenated moieties • some heterocycles • quaternary carbons • tertiary amines Favoring the chemical biodegradation (insertion of amides or esters)Chemical products should be designed so that at the end of their function they do not persist in theenvironment and instead break down into innocuous degradation products.
11. Real-Time Analysis for Pollution Prevention Real-time analysis is defined as the ability to monitor a transformation and act immediately upon it to prevent unwanted outcomes, by-products formation and to save energy. It is the goal of green analytical chemistry to measure chemicals without generating waste. Analytical procedure must be safer to human health and the environment. Analytical methodologies need to be further developed to allow for real-time in-process monitoring and control prior to the formation of hazardous substances.
12. Inherently Safer Chemistry for Accident Prevention Chemical accidents are generally very dangerous and with harmful consequences. The 12nd principle focuses on safety for the worker and the surrounding community where an industry/laboratory resides. When designing a process, it is best to avoid highly reactive chemicals that have potential to result in accidents. Substance and the form of a substance used in a chemical process should be chosen so as to minimize the potential for chemical accidents (releases, explosions, fires).
Green Chemical Synthesis Atom economyWaste prevention Less hazardousReduce steps IDEAL CHEMICAL Safer chemicals SYNTHESIS Catalysis Energy efficiency Renewable materials HOW TO ACHIEVE THIS GOAL?
Clean Chemical Synthesis Using Alternative Reaction Methods Alternative Reaction Media/Solvent-free • Supercritical Fluids • Ionic Liquids • Water • Polyethylene glycol (PEG) • Solvent free Alternative Energy Sources • Microwave • Ultrasound • Sunlight/UV Alternative/Advanced Chemical Instrumentations
Classical Batch Protocol Example: A + B = C1) Addition of 2) Mixing & 3) Extraction 4) Purificationraw materials HeatingA B A A C B B D C D B + C = A+ B =C ∞ B A pure C
Green Chemistry - Enabled Technologies new approaches Chemical synthesis Chemical engineeringFlow chemistry Micro-Wave Reactors Automated Chromatographic System Automated Automated Combinatorial Synthesizer Parallel Synthesizer
Green Chemistry - Enabled Technologies1) Addition of 2) Mixing & 3) Extraction 4) Purificationraw materials HeatingA B A A C B B D C =D B+C A+B = C B ∞ A pure C Micro-Wave assisted synthesis
MICROWAVE ASSISTED SYNTHESISApplication of microwaves in organic chemistry was published for first time in 1986. Now the microwave assisted synthesis hasemerged as new green and innovative tool in synthesis of organic and inorganic compounds. FAST AND HOMOGENEOUS HEATING OF IRRADIATED MATERIAL
What About Microwaves? Wavelenght (λ): 0.1 cm - 100 cm Frequency (ν) : 300 MHz - 300 GHz Waves Range of Frequency Very-High Frequencies (VHF) 30 - 300 MHz Ultra-High Frequencies (UHF) 300 - 3000 MHz Super-High Frequencies (SHF) 3 - 30 GHz Extremely-High Frequencies (EHF) 30 - 300 GHzThe microwaves used in domestic instruments and laboratory/industrialequipments belong to the area of the UHF (2450 MHz,12.25 cm)
What About Microwaves? Electric field Magnetic field Not responsible heating of heating ionic conductiondipolar polarization
MicroWaves – Heating by Ionic Conduction + - ions - - - + - - - - + + - - + - - - - - + - Absence of electric field Electric fieldCharged particles oscillate under the influence of oscillatingelectric field of microwaves and they collide with othermolecules and atoms. The kinetic energy of ions is lost in theform of heat.
MicroWaves – Heating by Dipolar Polarization unpolarized molecules with dipole ≠ 0 Polarized by an applied electric field• The dipoles orient themselves according to the direction of the electrical field.• The electrical field continuously changes.• This movement of molecules results into the collision and friction between moleculesthus the kinetic energy is lost as thermal energy
Microwaves – Heating by Dipolar Polarization Only polar materials exhibit microwave response and can be quicklyand efficiently heated. Polar materials (like water) have an elevated value of dielectricconstant (ε) and the dielectric tangent (tan δ, capability toabsorb the microwave energy and convert it into heat). Microwave heating effect is not a property of an individual molecule but a collective phenomenon of bulk.
Conventional Heating vs Alternative Energy Source flame oil bath heating mantle microwavesConventional Heating • You heat what you don’t want to heat (flask, vessel, • Bunsen burner reactor). • Oil bath • Necessity of heated up and cool down solvents for • Heating mantle reaction and apparatusAlternative Energy Sources • Microwave • Ultrasound Lower energy consumption • Sunlight / UV • Electrochemistry
Energy Consumption Energy consumption of the synthesis microwaves oil bath heating mantleThree ways to get the reaction done, but different energy bills to pay
Advantages of the Microwave Heating• Homogeneity of heating.• Speed of heating.• Clean, reproducible and easily automated. Microwave heating is efficiently used to force the organic chemical reactions!!!• Under microwave irradiations, high and intense temperature can beachieved very quickly.• According to Arrhenius equation, K =A∙e(-Ea/R∙T) Higher temperature = Higher reaction rate
Super Heating Effects and Hot Spots• High increase of rate of reactions with respect to conventional heating:additional non-thermal effects? • Ionic bond: 7.6 eV • Covalent [C-H]: 4.28 eV Non-thermal effects • Hydrogen bond: 0.04 – 0.44 eV have not be proven • Brownian motion: 1.7 x 10-2 eV • Microwaves: 1.6 x 10-3 eV• Under microwaves irradiation, solvents can be heated well above theirboiling points (super heating) for extended time. • Microwaves interact directly with molecules of entire volume of solvent leading to sudden and quick rise of temperature.• Formation of hot spots in reaction mixture due to the change ofdielectric properties of substances
Reaction Medium Dieletric Solvent tan δ Boiling point costant (ε) Hexane 1.9 n.d. 69° C Benzene 2.3 n.d. 80° C Chloroform 4.8 n.d. 61° C Acetic Acid 6.1 0.091 118° C Ethyl Acetate 6.2 0.174 77° C THF 7.6 0.059 66° CDichlorometane 9.1 0.047 40° C Acetone 20.6 0.042 56° C Ethanol 24.6 0.054 79° C Methanol 32.7 0.941 65° C Acetonitrile 36 0.659 81° C DMF 36.7 0.062 153° C DMSO 47 0.161 189° C Water 80.4 0.123 100° C
Greenness of Microwave Synthesis• Low energy consumption: homogeneity and speed of heating.• Faster reaction: minutes instead of hours or days (low energy consumption).• Atom economy: greater yield, lesser wastage.• Green solvents: H2O, EtOH, methanol and acetone are strongly responsive to microwave.• Less or no solvent: possibility to carried out concentrated reaction. Possibility of neat condition or supported reagents.• Rapid conditions screening: integrated on-line control guarantees safe operations.
Laboratory Microwave Systems – In Line Control
Industrial Microwave Reactors Microwave pilot plan
Industrial Microwave ReactorsIndustrial microwave reactor for large-scale production
List of Organic Reactions Carried Out by Microwave Irradiation • Reactions in liquid phase • Diels-Alder, etero- Diels Alder, Alder-Bong reactions • Synthesis and hydrolisis of esters and amides • Different aliphatic nucleophilic substitutions • Oxidation of alchol • Condensation of malonic esthers • Cyclocondensations of varius eterocycle compounds • Synthesis of organometallic compounds • Reactions in phase-transfer • Saponifications of hindered esthers • Decarboxilations • Solvent-free reactions • Aliphatic nucleophilic substitutions • Hydrolisis of esters and amides • Dehydration of alchols • Oxidation of alchols
Number of publications 0 1000 2000 3000 4000 5000 6000 70001985198619871988198919901991199219931994199519961997199819992000200120022003200420052006 Microwave Relevance in Chemistry200720082009201020112012
Example of Microwave Assisted Synthesis O O OH NaOH, MeOH OH O 60 °C, 8 h OH Yield: 100%HO OH NaOH, MeOH HO OH H μW, 100 °C, 15 min H Yield: 100% 1 2
Drug Production by Microwaves Assisted Synthesis Example: Sildenafil (Viagra®) OEt O CO2H OEt CO2HH2N N N H2N O2S N N 2 1 3 O H2 N O OEt O N tBuOK, BuOH EtO HN N N 85° C, 10 h N N 91% H N H O2S EtONa, EtOH N MW, 120° C, 10 min O2S N N Yield: 100% N 4 5
ConclusionsMicrowave assisted synthesis has become a common laboratory practice.Microwave assisted technique offers a simple, clean, faster, efficient and safemethods for chemical transformations.In recent years the technical developments have enormously extended thepossibilities and the applicability of the microwave irradiation for the chemicalsynthesis.All the advantages related to the use of microwave in organic chemistry areperfectly in harmony with the principles of green chemistry.
2. Atom Economy Low atom economy + + WasteRaw materials Product (by-products) High atom economy Molecular Weight atom (desired product) + economy = x 100 Molecular Weight (%) (all reactants) Raw materials Product Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product “Waste not, we don’t want it!”
Green Chemistry - Enabled Technologies1) Addition of 2) Mixing & 3) Extraction 4) Purificationraw materials HeatingA B A A C B B D C =D B+C A+B = C B ∞ A pure C Flow chemistry
Green Chemistry - Enabled Technologies1) Addition of 2) Mixing & 3) Extraction 4) Purificationraw materials HeatingA B A A C B B D C =D B+C A+B = C B ∞ A pure C Automated Chromatographic System
Microwaves – Heating by Dipolar Polarization Only polar materials exhibit microwave response and can be quicklyand efficiently heated. Polar materials (like water) have an elevated value of dielectricconstant (ε) and the dielectric tangent (tan δ, capability toabsorb the microwave energy and convert it into heat). Gases cannot be heated by microwave due to larger inter-particledistance (hence no friction).In solids, where molecules can not move freely, no heating occurs bymicrowaves. Microwave heating effect is not a property of an individual molecule but a collective phenomenon of bulk.
Microwave Apparatus: Magnetron• The cavity magnetron is a high-powered vacuum tube consisting of a cathodeand a anode placed in a magnetic field generated by a permanent magnet.• Magnetron generates microwaves using the interaction of a stream ofelectrons with the permanent magnetic field.
Microwave Apparatus: Waveguide Feed• A waveguide feed is a rectangular channel having reflective walls whichallows the transmission of microwaves from magnetron to microwave cavity.• It is made of sheet metal• These walls prevent leakage of radiations and increase the efficiency of theoven.
Microwave Apparatus: Oven Cavity Microwave cavity• Some area of oven cavity receives large amount of energy in the form ofelectric energy and in some it is neglected. For smoothing the incomingenergy in the cavity, a stirred is usually used.
Greenness of Microwave Synthesis: Solvent-Free Synthesis• According to green chemistry principles, more interest has now been focused solvent-free synthesis.• Solvent-free synthesis represent a clean, economical, efficient and safe approach that involve the exposure of neat reactants to MW irradiation coupled with the use of supported reagents.• The most commonly used supported reagents include mineral oxide as aluminas, silicas, zeolites.• The mineral oxides are very poor conductor of heat but they absorb microwave radiation very effectively determining a significant improvement in temperature, homogeneity and heating rates.
Reaction vessel • The preferred reaction vessel for microwave is a tall beaker loosely covered with a capacity much greater than the volume of the reaction mixture. • Vessels are made of material transparent to microwaves, such as teflon, polystyrene and glass. • No metallic container can be used as it gets heated soon due to preferential absorption10 ml 35 ml and reflection of rays.
Conventional Heating vs Alternative Energy Source flame oil bath heating mantle microwavesConventional Heating • You heat what you don’t want to heat (flask, vessel, • Bunsen burner reactor). • Oil bath • Necessity of heated up and cool down solvents for reaction • Heating mantle and apparatus
Conventional Heating vs Alternative Energy Source flame oil bath heating mantle microwavesAlternative Energy Sources • Microwave • Ultrasound Lower energy consumption • Sunlight / UV • Electrochemistry